The ancestor of the hairball

The first entry in the “cite the oldest paper” competition is in, a suggestion from Pam Silver. Ever the student’s friend, Pam also wanted to offer a clue: there is at least one paper written in French, published in 1959, that has a very clear relationship with systems biology. Can you find it? [Remember, it is the difference between your age and the age of the publication that matters, not the absolute age of the paper. Anyone under 38 would spring into the lead with a paper published in 1959.]

Pam’s entry is older (Srb, AM and Horowitz, NH, 1944. The ornithine cycle in Neurospora and its genetic control. J. Biol. Chem154 129-139), but also perhaps more controversial. Published only three years after Beadle and Tatum used Neurospora to demonstrate the connection between genes and enzymes, and at a time when the nature of genes was uncertain — it was suspected that they consisted of nucleoprotein complexes, or at least contained such complexes as essential elements — this paper describes the existence of a network of genes whose products perform a complex set of biochemical reactions, producing arginine.

Now one of the less fashionable model organisms, but once a supremely important one, Neurospora first came to scientific notice as a major pest in bakeries, growing as large salmon-colored clouds on the bread loaves. The menace was later reduced somewhat by the routine use of mold inhibitors, but by that time scientists were hooked. In the ’20s it was discovered that what makes Neurospora so good at thriving in bakeries is that the spores survive high heat (indeed, require heat to germinate). It also turns out to be the first organism that colonizes areas that have been semi-sterilized by volcanic eruptions — “producing great masses of brilliant conidia of bizarre appearance”. [Google Images has failed me on this one, if anyone can find some “brilliant conidia” please send me a picture or a link]. Early scientists who collected Neurospora species in the tropics ran in to some difficulty: it had a tendency to grow straight through the cotton wool they were using to close the tops of their tubes. But once they got it into a cool, dry climate, it became more manageable.

Neurospora was quickly recognized as an excellent genetic organism. The NIH has a list of its advantages: the big one, apart from convenience and ease of growth, is that the 8 haploid ascospores (resulting from two meiotic divisions and a mitotic division) are easy to separate, and arranged in an ordered fashion. As Beadle and Tatum found, this means that when you damage the DNA of a Neurospora strain with X-rays, you can very quickly identify and analyze progeny that have mutations. The first type of mutation they looked for was one that created a novel dietary requirement — mutants that would no longer grow on minimal medium, but needed a supplement of vitamin B6, for example. They found three such mutants, which were then shown by segregation analysis to be mutations in single genes involved in the synthesis of the newly required nutrient. And the link between genes and biochemistry was born.

Srb and Horowitz, like Beadle and Tatum, were at Stanford, had access to Neurospora, and were quickly able to go looking for their own mutants. They found not just one, but several mutants that were all deficient in arginine synthesis — they didn’t grow on minimal media, but did grow on media supplemented with arginine. They showed that the mutants were in different genes by crossing them and looking at how the defect segregated. And then they looked at whether arginine precursors could rescue growth.

The biochemical steps involved in the synthesis of arginine in liver had been worked out by Krebs and Henseleit in 1932. There was, at the time, no reason to think that arginine synthesis in Neurospora would be similar. But it was — in retrospect, this was an early hint that much of metabolism had been invented once, then conserved. Some of Srb and Horowitz’s mutant strains grew on ornithine, others on citrulline; for others, nothing but arginine would do. Srb and Horowitz were thus able to piece together a network of genes that connected with the biochemical steps involved. In that sense, Srb and Horowitz’s work was the first step towards the hairballs that we struggle with today. Appropriate, perhaps, that it all started with something that looks like this.

I’m happy to claim this as one of the deep roots of systems biology. How about you? Answers in the comments section, please.